Novel (xcex1-aminophosphino)peptide derivatives, process for their preparation and their therapeutic applications
The perception, transmission and regulation of nociceptive influxes come under the influence of several endogenous neurotransmitters. In 1975, Hugues et al., Nature, 258, 577, 1975 revealed the enkephalins, two pentapeptides originally isolated from mammalian brains, which are involved in the transmission of pain influxes. Enkephalins are associated with at least two classes of receptors: the xcexc and xcex4 opioid sites (Pert, Sciences, 179, 1011, 1973) whose roles and locations are different. Their antinociceptive properties have been demonstrated by Belluzi et al., Nature, 260, 625, 1976. However, the analgesia induced by the administration of exogenous enkephalins is very fleeting, on account of the rapid metabolization of these peptides. Enkephalin analogues made resistant to enzymatic degradation by chemical modifications have been synthesized, but their side effects are similar to those of morphine.
Enkephalins are physiologically degraded by two types of enzymatic activities which metabolize enkephalins in vivo: neutral endopeptidase (EC 3.4.24.11, also known as NEP) which cleaves the Gly3-Phe4 bond, and aminopeptidase N (EC 3.4.11.2, also known as APN) which cleaves the Tyr1-Gly2 bond (review in Roques et al., Pharmacol. Rev., 45, 87-146, 1993).
Prodrugs which possess analgesic and antidepressant activities after intravenous or oral administration (Noble et al., J. Pharm. Exp. Ther., 261, 181, 1992; Baamonde et al., Eur. J. Pharmacol., 216, 157, 1992) are known, these being described in European patent EP 0,487,620 and in Fournixc3xa9-Zaluski et al., J. Med. Chem., 35, 2473, 1992. However, these compounds do not satisfy the concept of mixed inhibitors, on account of their structure in which an APN inhibitor and an NEP inhibitor are associated by means of a disulphide bridge. These compounds are then reduced by cerebral reductases and each act on their specific target.
According to patent application WO 95/35302 and Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 11, pp 1257-1260, 1996, certain phosphinic acid derivatives are known which have, respectively, an inhibitory activity on endothelin conversion enzyme (ECE) and a mixed inhibitory activity on angiotensin conversion enzyme (ACE) and on neutral endopeptidase (NEP). These compounds are useful in the treatment of cardiovascular diseases.
One of the objects of the invention is to provide novel compounds which behave as true mixed inhibitors of APN and of NEP, and which are capable of jointly inhibiting the two enzymatic activities responsible for the degradation of enkephalins and of manifesting their pharmacological properties after intravenous, cutaneous or oral injection.
These compounds have certain properties of morphinic substances, in particular analgesia, beneficial effects on behaviour (antidepressants, sedatives, anxiolytic agents, inhibition removers and promnesic agents), and peripheral effects (antidiarrhoeic, antitussive, hypotensive, anti-inflammatory, etc. effects). Furthermore, one advantage of these compounds is that they have none of the harmful effects of morphinic agents (tolerance, physical and psychic dependency, respiratory depression, intestinal stasis, etc.).
The present invention therefore provides an (xcex1-aminophosphino)peptide of general formula (I) 
in which
R1 and R2 each represent a hydrogen atom or alternatively R1 and R2, taken together, form an unsaturated group of formula Rxe2x80x2 (Rxe2x80x3)Cxe2x95x90, in which,
Rxe2x80x2 represents a phenyl group monosubstituted in position 2 with a hydroxyl group, or alternatively a phenyl group disubstituted, in position 2, with a hydroxyl group and, in position 4 or 5, either with a halogen atom or with a nitro group, or with a hydroxyl group, or with an alkoxy group xe2x80x94OR9,
Rxe2x80x3 represents a phenyl group, a phenyl group substituted by 1 to 5 halogen atoms or a heterocyclic aromatic group,
hereinafter, the terms R9 and R10, used for the definition of radicals, each represent an alkyl group of 1 to 6 carbon atoms,
R3 represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, it being possible for these last two groups to be substituted with:
a hydroxyl group or an alkoxy group xe2x80x94OR9,
a phenyl group or a benzyl group,
a sulphanyl group, an alkylsulphanyl group xe2x80x94SR9 or an alkylsulphanyl group oxidized on the sulphur atom xe2x80x94S(O)R9,
an amino group, a group xe2x80x94NHR9 or xe2x80x94NR9R10, optionally oxidized on the nitrogen atom, or
a guanidino group H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94,
a cycloalkyl or cycloalkylmethyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
a halogen atom,
a hydroxyl group, an alkoxy group xe2x80x94OR9,
an alkylsulphanyl group xe2x80x94SR9 or an alkylsulphanyl group oxidized on the sulphur atom,
an amino group or a group xe2x80x94NHR9 or xe2x80x94NR9R10 optionally oxidized on the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted with a heterocyclic aromatic or saturated group, it being possible for the hetero atoms to be oxidized in the form of N-oxide or S-oxide,
R4 represents
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms,
a cycloalkyl group, a cycloalkylalkyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
an alkyl group of 1 to 6 carbon atoms,
a halogen atom,
a hydroxyl group or an alkoxy group xe2x80x94OR9,
a trifluoromethyl group,
a nitro group,
R5 represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, it being possible for these last two groups to be substituted with:
a hydroxyl group or an alkoxy group xe2x80x94OR9,
a phenyl group or a benzyl group,
a sulphanyl group, an alkylsulphanyl group xe2x80x94SR9 or an alkylsulphanyl group oxidized on the sulphur atom xe2x80x94S(O)R9,
an amino group, a group xe2x80x94NHR9 or xe2x80x94NR9R10, optionally oxidized on the nitrogen atom, or
a guanidino group H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94,
a cycloalkyl or cycloalkylmethyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
a halogen atom,
a hydroxyl group, an alkoxy group xe2x80x94OR9,
an alkylsulphanyl group xe2x80x94SR9 or an alkylsulphanyl group oxidized on the sulphur atom,
an amino group or a group xe2x80x94NHR9 or xe2x80x94NR9R10 optionally oxidized on the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted with a heterocyclic group, it being possible for the hetero atoms to be oxidized in the form of N-oxide or S-oxide,
R6 and R7 represent, independently of each other,
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms, which can be substituted with:
a hydroxyl group or an alkoxy group xe2x80x94OR9,
a sulphanyl group, an alkylsulphanyl group xe2x80x94SR9 or an alkylsulphanyl group oxidized on the sulphur atom xe2x80x94S(O)R9,
an amino group or an alkylamino group xe2x80x94NHR9,
a guanidino group H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94, or
a carboxyl group or an alkyloxycarbonyl group xe2x80x94COOR9,
a phenyl group, a benzyl group, which can be substituted on the phenyl group by 1 or 2 of the following substituents:
a halogen atom,
a phenyl group,
a hydroxyl group or an alkoxy group xe2x80x94OR9,
an alkylsulphanyl group xe2x80x94SR9 or an alkylsulphanyl group oxidized on the sulphur atom xe2x80x94S(O)R9,
R6 and R7 together represent a saturated or unsaturated 5- or 6-membered ring comprising 1 or 2 hetero atoms, taken from among oxygen, sulphur and nitrogen,
R8 represents,
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms,
a phenyl group, a benzyl group,
n is equal to 0 or 1,
with the exception of methyl N-[2-[[(aminomethyl) (methoxy)phosphinyl]methyl]-4-methyl-1-oxopentyl]-(1,1xe2x80x2-biphenyl-4-yl)-L-alaninate hydrochloride.
In the context of the invention the terms below have the following meanings:
an alkyl group is a linear or branched, saturated hydrocarbon chain,
an alkenyl group is a linear or branched hydrocarbon chain containing unsaturation,
a cycloalkyl group is a cyclic hydrocarbon chain comprising 3 to 7 carbon atoms,
a cycloalkylalkyl group is a cycloalkyl group linked to an alkyl group, this alkyl group comprising 1 to 6 carbon atoms,
a cycloalkylmethyl group is a cycloalkyl group linked to a methyl group,
a heterocyclic group is a cyclic, aromatic or non-aromatic, 5- or 6-membered hydrocarbon chain comprising 1 or 2 hetero atoms chosen from oxygen, sulphur and nitrogen atoms.
In the context of the invention, the halogen atoms are preferably chlorine and fluorine.
When a phenyl group is substituted with a phenyl group, this preferably takes place in position 4 in order to form a biphenyl group (which is also written: [1,1xe2x80x2-biphenyl]).
The subject of the present invention is also the addition salts with pharmacologically acceptable acids of the compounds of formula (I) for which R1 and R2 are hydrogen atoms.
A preferred category of compounds according to the invention are those for which the radicals of formula (I) have the following meanings:
R1, R2, R4 and R8 represent hydrogen atoms,
n is equal to 0,
R3 represents
an alkyl group of 1 to 6 carbon atoms, which can be substituted with an alkoxy group xe2x80x94OR9, a sulphanyl group or an alkylsulphanyl group xe2x80x94SR9,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group xe2x80x94OR9 or an alkylsulphanyl group xe2x80x94SR9,
R5 represents
an alkyl group of 1 to 6 carbon atoms, which can be substituted with an alkoxy group xe2x80x94OR9, a sulphanyl group or an alkylsulphanyl group xe2x80x94SR9,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group xe2x80x94OR9 or an alkylsulphanyl group xe2x80x94SR9,
a biphenylmethyl group,
R6 represents
an alkyl group of 1 to 6 carbon atoms, which can be substituted with an alkoxy group xe2x80x94OR9, a sulphanyl group or an alkylsulphanyl group xe2x80x94SR9,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group xe2x80x94OR9 or an alkylsulphanyl group xe2x80x94SR9,
a biphenylmethyl group.
The compounds of formula (I) can have from 1 to 5 chiral atoms. The compounds of the invention can exist in different isomeric forms, including the form of enantiomers and diastereoisomers. The present invention includes these different forms as well as mixtures thereof, including racemic mixtures.
The carbon bearing the radical R6, when R6 is other than a hydrogen atom, is advantageously of (S) absolute configuration.
The compounds of the invention of formula (I) can be prepared according to the processes described in Appendices 1, 2 and 3.
In the description of the process, the radicals A1, A2 and A3 have the following meanings:
A1 represents a biphenylmethyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a fluorenylmethoxycarbonyl group,
A2 represents a hydrogen atom, an alkyl group such as methyl or ethyl, or a benzyl group,
A3 represents a methyl, ethyl, tert-butyl or benzyl group.
The compounds of formula (Ia), (Ib) and (Ic), which are compounds of formula (I) according to the invention, are prepared according to the process represented in Appendix 1. R3, R4, R5, R6, R7, Rxe2x80x2 and Rxe2x80x3 have the meanings given in formula (I). According to this process, a hydroxyphosphinylpropanoic acid derivative of formula (IVb) is reacted with an amino acid derivative of formula (III), in the presence of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), in an organic solvent such as dimethylformamide. The compound of formula (III) may be used in the form of a salt, such as the p-toluenesulphonic acid salt. It is then particularly advantageous to work in the presence of a base such as a tertiary amine, for instance diisopropylethylamine. This reaction makes it possible to obtain a compound of formula (IIa).
In the case where R5 represents, in the final product of formula (I), a biphenylmethyl group, the process is performed according to a variant during this step, which consists in carrying out the coupling described above under the same operating conditions, starting with the compound of formula (IVb) and the compound of formula (III), in which the radical R5 firstly represents a (4-bromophenyl)methyl group. The compound of formula (IIa) thus obtained is then reacted with phenylboronic acid in a solvent such as a toluene/methanol mixture and in the presence of tetrakis(triphenylphosphine)palladium and sodium carbonate, in order to obtain the compound of formula (IIa), in which R5 is a biphenylmethyl group.
The compound of formula (IIa) is used to prepare the compound of formula (Ia), in which the three amine, phosphinate and carboxylate functions are deprotected simultaneously or successively. The carboxyl function can be deprotected in order to give a compound of formula (IIb), for example by saponification. The phosphinate function can be deprotected in order to give a compound of formula (IIc). The amine function can be deprotected in order to give a compound of formula (Ia), for example by catalytic hydrogenation or acidic hydrolysis. This is the alternative C, represented in Appendix 1.
According to an alternative mode of preparation, the compound of formula (Ia) can be obtained directly from the compound of formula (IIa) by catalytic hydrogenation, in particular when A1 represents a benzyloxycarbonyl group, A2 represents a benzyl group and A3 represents a benzyl group. This is the alternative B, represented in Appendix 1.
In order to prepare the compound of formula (Ib), in which R4 and R8 are other than a hydrogen atom, the compound of formula (IIc) in which the amine function is protected, is esterified according to methods known to those skilled in the art, which amounts to introducing the radicals R4 and R8, respectively, on the phosphinate function and on the carboxylate function. An alcohol R4OH, in which R4 has one of the meanings given in formula (I) except for hydrogen, can thus be condensed on a compound of formula (IIc), in the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC) and a base such as dimethylaminopyridine (DMAP), on this compound of formula (IIc). Lastly, the amine function is deprotected.
According to an alternative mode of preparation of the compound of formula (Ib), in which the radicals R4 and R8 each represent one of the possible substituents of A2, respectively, with the exclusion of a hydrogen atom, and of A3, the compound of formula (Ib) can be obtained directly by deprotecting only the amine function of the compound of formula (IIa). This is the alternative A, represented in Appendix 1.
In order to prepare the compound of formula (Ic), a ketone Rxe2x80x2 (Rxe2x80x3)Cxe2x95x90O is condensed with a compound of formula (Ib) if R4 and R8 are other than a hydrogen atom, and with a compound of formula (Ia) if R4 and R8 represent a hydrogen atom, these ketones Rxe2x80x2 (Rxe2x80x3)Cxe2x95x90O being obtained by Fries rearrangement of the corresponding esters Rxe2x80x2CO2Rxe2x80x2.
The compounds of formula (III), in which n can be equal to 0 or 1, R6 and R7 taking one of the meanings given in formula (I), represent a natural or non-natural xcex1- or xcex2-amino acid. They can be synthesized according to the standard methods that are well known to those skilled in the art.
The compounds of formula (IVb) can be prepared according to the processes described in Appendices 2 and 3. The compound of formula (IVb) is obtained from the compound of formula (IVa) by a standard saponification.
The final step of the process is represented in Scheme 1 of Appendix 2. According to this final step of the process, a phosphonic acid derivative of formula (VIb) is added to an acrylic ester derivative of formula (V), in the presence of N,O-bis(trimethylsilyl)acetamide, without solvent or in an inert organic solvent such as acetonitrile.
The compound of formula (VIb) is obtained by indirect or direct synthesis, represented in Scheme 2 of Appendix 2:
via the indirect route, the process consists in treating diphenylmethylamine with phosphonous acid and in reacting the diphenylmethylamine, in the form of the phosphonous acid salt obtained, with an aldehyde R3CHO in anhydrous ethanol in order to obtain a compound of formula (X). The amine function of this compound of formula (X) is then deprotected in water, optionally acidified with an inorganic acid, such as hydrochloric acid or hydrobromic acid, and the compound obtained is then treated with propylene oxide in order to lead to the compounds of formula (VII), which are finally acylated in order to obtain a compound of formula (VIa),
via the direct route, the process consists in treating diphenylmethylamine hydrochloride with phosphonous acid and an aldehyde R3CHO, this reaction being carried out in a mixture of ethanol and water at reflux.
The compounds of formula (V) can be obtained by two methods, which are represented in Appendix 3, respectively in Schemes 3 and 4:
according to the first process (Scheme 3), a halide, and preferably a bromide, of alkyl or of aralkyl R5X is reacted with triethyl phosphonoacetate in the presence of sodium hydride in order to obtain a compound of formula (VIII), which is reacted with formaldehyde, in the presence of potassium carbonate, in order to obtain a compound of formula (V),
according to the second process (Scheme 4), the compounds of formula (V) are obtained by a Mannich reaction on a monoester of a malonic acid of formula (IX).
Another aspect of the invention relates to the compounds of formula (IIa), which are useful in particular as synthetic intermediates for the preparation of the compounds of formula (I). They can also be in the form of isomers, including the form of enantiomers and diastereoisomers and mixtures of these different forms, as well as in the form of addition salts.
However, the following compounds, described in B. P. Morgan et al., xe2x80x9cdifferential binding energy: a detailed evalutation of the influence of hydrogen-bonding and hydrophobic groups on the inhibition of thermolysin by phosphorus-containing inhibitors, Journal of the American Chemical Society (1991), 113, 297-307, are excluded:
methyl N-[2-[[methoxy[[[(phenylmethoxy)carbonyl)amino]-methyl]phosphinyl]methyl]-4-methyl-1-oxopentanyl]-L-alaninate,
methyl N-[-[[methoxy[[[(phenylmethoxy)carbonyl]amino]methyl]phosphinyl]methyl]-4-methyl-1-oxopentanyl]-L-glycinate,
methyl N-[-[[methoxy[[[(phenylmethoxy)carbonyl]amino]methyl]phosphinyl]methyl]-4-methyl-1-oxopentanyl]-L-phenylalaniante and,
methyl N-[-[[methoxy[[[(phenylmethoxy)carbonyl]amino]methyl]phosphinyl]methyl]-4-methyl-1-oxopentanyl]-L-leucinate.
The compounds of general formula (I) thus obtained are in the form of isomers, including the form of enantiomers, diastereoisomers and mixtures of these different forms, including racemic mixtures. The compounds of formula (I), which are optically pure, are obtained by semi-preparative HPLC separation (Chromasil C8, 10 mm, 20xc3x97250 mm, acetonitrile/water, 15 ml/min).
They can also be obtained by resolution, starting with a chiral amine of the phosphinic acid derivative of formula (VIb), in which A2=H, followed by diastereoselective Michael addition, in the presence of chiral inducers, which leads to the compounds of formula (IV), which are of fully defined stereochemistry.
The examples which follow are intended to illustrate the preparation of a number of compounds of the invention. The elemental analyses and the NMR spectra confirm the structures of the compounds obtained.
In the compound names, the hyphen xe2x80x9c-xe2x80x9d forms part of the name, and the line xe2x80x9c_xe2x80x9d serves merely to indicate the end-of-line break; it should be removed if it is not at the end of a line and it should not be replaced either by a normal hyphen or by a space.
In the examples which follow, the racemic mixture obtained for each of the compounds can be separated on a Chromasil C8 preparative column (10 mm, 20xc3x97250 mm, 15 ml/min) with an acetonitrile/water mixture. The amino acids used in these syntheses have an (S) absolute configuration and a mixture of four diastereoisomers is thus obtained. By convention, these diastereoisomers are referred to as A, B, C and D in order of increasing retention time. The retention times of the compounds are collated in the table.